In our Forum discussion “journal club” series, the editors of Schizophrenia Bulletin provide access to the full text of a recent article. A short introduction by a journal editor gets us started, and then it's up to our readers to share their ideas and insights, questions, and reactions to the selected paper. So read on….

In the September 2010 issue of Schizophrenia Bulletin, Remington and Kapur review preclinical and clinical literature on the effects of continuous versus intermittent antipsychotic drug treatment. This review paper draws interesting and provocative conclusions that challenge the established clinical lore regarding the optimal dosing of antipsychotic drugs. The authors point out that while a certain amount of D2 occupancy is critical for the antipsychotic response, continuous high occupancy is not needed. This would suggest that non-continuous antipsychotic dosing would be as effective as continuous dosing, and data from targeted antipsychotic treatment and drug holiday treatment trials support this approach.

Any treatment strategy that reduces total exposure to drugs has advantages and likely reduces side effects. However, does continuous treatment do more harm by modulating the responsivity to the treatment following extended use? This seems unlikely, although a thought-provoking question. The paper also challenges the benefit of extended release formulations. It is somewhat surprising that after half a century of antipsychotic medications, some of the fundamental questions such as frequency of dosing remain. As suggested by the authors, the field needs to focus on several questions in this context. What are effective alternatives to continuous antipsychotic drug treatment? Is the shift toward slow-release formulations wrong-headed? Should one invest in compounds with short half-lives?

Remington and Kapur present a new and impressive challenge...
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Remington and Kapur present a new and impressive challenge to the assumption that continuous D2 occupancy is optimal for the treatment of schizophrenia, a belief that has guided antipsychotic development and dosing over the past few decades and which is behind current advocacy of depot antipsychotics and sustained release formulations. As the authors note, there is a long history to this debate. Back in the 1970s, the etiology of tardive dyskinesia (TD) was believed to involve antipsychotic-induced dopamine supersensitivity, as evidenced by increased D2 receptor density and behavioral response to dopamine agonists (Tarsy and Baldessarini, 1977). This led to studies of intermittent and targeted administration of antipsychotics, but the prolonged discontinuation of treatment resulted in unacceptable rates of relapse (Carpenter et al., 1990). In addition, intermittent dosing did not reduce the incidence of tardive dyskinesia and may even have increased risk (Goldman and Luchins, 1984; Jeste and Wyatt,1982; van Harten et al., 1998). Subsequent work linked TD to neurotoxic factors, including glutamatergic excitotoxicity and oxidative stress, which could better account for risk and time course of TD than the model of dopamine supersensitivity (Goff et al., 1995; Tsai et al., 1998).

Even if efforts to reduce the risk of TD with intermittent dosing were unsuccessful, the possibility that clinical outcomes could be improved by preventing antipsychotic tolerance remains highly relevant. Of note, the phenomenon of supersensitivity does not appear to be restricted to first-generation agents. Remington and Kapur provide evidence of tachyphylaxis in response to continuous administration of olanzapine (Samaha et al., 2008). The potential negative clinical consequences of chronic D2 blockade may be greater than just a loss of antipsychotic efficacy. For example, Castner and colleagues (Castner et al., 2000) demonstrated a significant reduction in cognitive performance over a six-month period when monkeys were exposed to continuous treatment with haloperidol, an effect attributed to D1 receptor downregulation in response to D2 blockade. Studies in first-episode patients have found a relationship between cumulative antipsychotic exposure and gray matter volume loss (Cahn et al., 2002; Ho et al., 2003). In addition, the findings of volume loss and neurotoxic glial changes in brains of monkeys chronically exposed to olanzapine and haloperidol remain unresolved (Dorph-Petersen et al., 2005; Konopaske et al., 2007). While the clinical relevance of these potential adverse consequences of chronic antipsychotic treatment remain uncertain, they add urgency to issues raised by Remington and Kapur, much as concerns about tardive dyskinesia propelled early efforts at intermittent therapy.

As the authors point out, tolerance could account for what appears to be increasing resistance to antipsychotics over time, although, from a clinical perspective, extended periods of drug discontinuation are not associated with improved response when patients resume therapy. First-episode patients may be an ideal population to test new approaches designed to reduce tolerance to D2 receptor blockade. Even in first-episode patients, targeted treatment in which patients remain off treatment until the first sign of relapse is not the answer, as demonstrated by a recent negative trial of intermittent dosing in first-episode patients (Gaebel et al., 2010). As Remington and Kapur emphasize, biological heterogeneity complicates the problem of identifying an ideal dosing strategy. For example, drug discontinuation studies in first-episode patients have demonstrated a very wide inter-individual variability in time to relapse—some patients relapse within days or weeks, while others may remain stable for over a year (Gitlin et al., 2001). The prolonged delay before relapse following drug discontinuation raises questions as to what mechanism is responsible for persistence of antipsychotic effect and what biochemical process triggers relapse. Answers to these questions might guide the development of a personalized medicine approach to intermittent maintenance treatment.

Once a brief course of continuous D2 blockade has achieved remission of psychosis, it is also unclear how long a patient must be off medication to reverse dopamine supersensitivity or to halt a putative neurotoxic process. One study in mice suggested that drug holidays longer than 10 weeks might be needed to reverse D2 receptor upregulation (Bannet et al., 1980). Remington and Kapur propose, based on their recent work, that frequent, brief interruptions in treatment may be a more reasonable approach than prolonged drug holidays. For example, they have preliminary clinical evidence (in press) suggesting that alternate-day dosing may preserve efficacy. In addition, preclinical evidence from their laboratory suggests that transient daily D2 blockade may produce less tolerance than continuous daily D2 blockade (Samaha et al., 2008). This approach would favor once-daily dosing of short half-life antipsychotics. Whether these approaches, by avoiding dopamine supersensitivity, will prevent relapse while preserving antipsychotic efficacy remains to be demonstrated. The potential value of experimenting with drug administration schedules to minimize tolerance is supported by recent preliminary evidence with the glutamatergic partial agonist, D-cycloserine, which produced persistent improvement in negative symptoms when administered once-weekly (Goff et al., 2008). It is essential to establish whether animal models of antipsychotic tolerance predict clinical outcomes. If so, the proposal by Remington and Kapur to avoid continuous D2 blockade could substantially improve antipsychotic treatment.

Remington and Kapur (Remington and Kapur, 2010) cling to the outmoded notion that D2 receptor blockade is the only means to achieve an antipsychotic response. Their only justification offered for this view is that all currently approved antipsychotic drugs for schizophrenia have some D2 receptor antagonism. This is accurate, but misleading. It should be clear to them by now that this unfortunate state of affairs is not because we lack antipsychotic drugs that could treat psychosis without directly blocking D2 receptors, but because of the time, money, and effort needed to gain approval for a new drug. This fact of life in the drug discovery and approval world would be true even for a clone of haloperidol.

There are many reasons to believe that there are other bases for treating psychosis that do not involve D2 receptor blockade but are not yet approved as monotherapies. It is already known that D2 receptor blockade is a contributor, and an important one, to antipsychotic drug action of drugs like clozapine, olanzapine, quetiapine, and risperidone, but this is not the whole story. What makes these and related drugs effective and tolerable is 5-HT2A receptor blockade, a core component of aripiprazole, asenapine, clozapine, iloperidone, olanzapine, quetiapine, risperidone, ziprasidone, and lurasidone (yet another serotonin-dopamine multi-receptor targeting drug for which FDA approval is pending) (Meltzer et al., 1989; Meltzer and Huang, 2008). Clozapine and quetiapine are not approved for treatment of L-DOPA-induced Parkinson disease psychosis (PDP) due to an inadequate investment in the effort to obtain an indication, but are both effective treatments, and at doses where no D2 receptor blockade is likely (Meltzer et al., 2010). Kapur, at least, must be aware of this because of his championing of the importance of the rapid dissociation of the very weak D2 DA receptor blockers from the D2 receptor (Kapur and Seeman, 2001). The selective 5-HT2A inverse agonist (antagonists of stimulated and constitutive 5-HT2A receptor activation), pimavanserin (ACP-103), has been shown to be superior to placebo to treat delusions and hallucinations in PDP patients (Meltzer et al., 2010). A failed Phase 3 trial has delayed but will not stop research with this important agent, and additional Phase 3 studies are in progress. All efforts to show that quetiapine is superior to placebo in controlled trials in this disorder have also failed, but none have been negative. Nevertheless, it is the first line of treatment because tens of thousands of patients have benefited from it. Failure to find definitive proof of efficacy in the absence of clearly negative studies does not rule out efficacy.

We have recently presented evidence at the Society for Neuroscience and ACNP that pimavanserin, which, as noted above, is effective in PDP, can speed up and enhance the efficacy of a sub-effective dose of risperidone in patients with schizophrenia who have experienced an acute exacerbation of psychosis. This will be submitted for publication shortly. M100907 and SR43469B are other 5-HT2A inverse agonists which have shown superior efficacy to placebo in small clinical trials (Meltzer and Huang, 2008; Meltzer et al., 2010). There is genetic (Maier et al., 2008), postmortem (Arora and Meltzer, 1991), and PET study data indicating the importance of 5-HT2A receptors in schizophrenia and its prodromal phase. It is highly likely that the 5-HT2A receptor blockade will be most useful in the clinic as a means of potentiating the action of many, if not all, of the abovementioned atypical APDs, where too much D2 receptor blockade is unwanted and unnecessary, and 5-HT2A receptor blockade is also achieved. Equal or better efficacy at lower doses will show the beneficial effects of full 5-HT2A receptor blockade as well as a weak as necessary D2 receptor blockade.

It is difficult to understand how Kapur and Remington can dismiss the abundant, unequivocal, undisputed evidence showing markedly greater ability of the 5-HT2A inverse agonists, e.g., M100907 and ACP-103, compared to D2 antagonists, for example, haloperidol, to block NMDA receptor antagonist-induced locomotor activation in rodents versus amphetamine-induced locomotor activity (Schmidt and Fadayel, 1996; Maurel-Remy et al., 1995; Meltzer et al., submitted). As shown by Maurel-Remy et al. (Maurel-Remy et al., 1995), haloperidol more potently blocked amphetamine (2.5 mg/kg i.p.) than PCP (20.0 mg/kg s.c.) induced locomotor activity, with inhibitory doses of 0.04 and 0.09 mg/kg s.c., respectively, while clozapine was 20 times more effective to block the locomotor effect of PCP (0.04) than that of amphetamine. The locomotor stimulating effects of the NMDA receptor antagonists PCP, MK-212, or ketamine are considered to be superior as a model of the psychosis of schizophrenia than the response due to amphetamine (Large, 2007).

Other components of the atypical APDs are likely to contribute to their antipsychotic action. These include, but are not limited to, 5-HT1A partial agonism and α2 adrenoceptor antagonism (Meltzer et al., 2008; Large, 2007). mGluR2/3 agonists are another class of non-DA receptor blockers which are effective in the NMDA receptor model and for which there is preliminary clinical evidence for efficacy (Marcus et al., 2010). Efforts by other colleagues of Remington and Kapur's to show that mGluR2/3 agonists work via their ability to modulate D2 receptors (Patil et al., 2007) have not been replicated (Seeman et al., 2009). 5-HT2C agonists are also promising candidates for monotherapy to treat psychosis or as a means of augmenting antipsychotic drugs, comparable to what has been reported for 5-HT2A antagonists (Fell et al., 2009; Marquis et al., 2007).

It is important for clinicians to understand the limits of the D2 receptor model. Remington and Kapur have staked too much on it, calling into question their elaborate clinical decision making proposals concerning how to use the most widely used antipsychotic drugs, which are much more complex than selective D2 antagonists. To paraphrase Shakespeare, there are more components to antipsychotic drug action, Remingon and Kapur, than are dreamt of in your model.

Antipsychotic Dosing: How Often Is Too Much and How Infrequent Is Too Little?
Optimal dosing of antipsychotics in patients with schizophrenia has remained a formidable challenge. This has been true in drug development, regulatory trial design, and clinical practice. Questions that have remained unresolved include: the dose requirements in the acute and maintenance phases of schizophrenia, whether overstepping the neuroleptic threshold that is associated with the emergence of extrapyramidal side effects is helpful in non-responding patients, and whether dose or blood levels are useful for predicting antipsychotic response (Baldessarini and Davis, 1980; Janicak and Davis, 1996; Citrome et al., 2009; Liu and De Haan, 2009; Hartung et al., 2008; Barbui et al., 2007; Yamin and Vaddadi, 2010).

In their very scholarly and thought provoking article, Remington and Kapur (Remington and Kapur, 2010) contribute to the ongoing debate about how high the antipsychotic dose should be by raising the additional issue of how frequent dosing should occur. The authors raise the questions whether and to what degree continuous antipsychotic dosing and, thereby, continuous dopamine blockade, is necessary, helpful, or possibly even detrimental for the treatment of psychosis (Remington and Kapur, 2010; Samaha et al., 2008). They review the preclinical and clinical body of evidence for the effects of continuous versus extended versus intermittent antipsychotic dosing. While intermittent (or targeted) dosing—defined by long treatment gaps until early signs of relapse emerge—has repeatedly been shown to be inferior to continuous dosing in chronic (Kane, 1996) and even long-term, stabilized, first-episode patients (Gaebel et al., 2010), the authors make the point that continuous dosing might also be associated with diminished efficacy. As a result, extended dosing, defined as a dosing schedule that has a small and finite gap in dosing, is proposed as a compromise between the loss of efficacy due to complete absence of dopamine blockade and the reduced efficacy due to hypersensitized receptors following continuous dopamine blockade.

The argument is made that reducing response rates and increasing relapse rates during the course of schizophrenia are not only due to an enrichment of more chronic, non-responsive patients, or possibly detrimental, biological effects of the continued illness. Rather, the antipsychotic-induced, compensatory dopamine receptor upregulation might lead to tolerance and reduced responsiveness, poorer illness course, and the need for higher antipsychotic doses compared to the treatment of first-episode patients (Remington and Kapur, 2010). In fact, the development of partial dopamine D2 agonists was an attempt at restoring the physiologic dopamine transmission (Grunder et al., 2003). However, in addition to animal data (Seeman, 2008), the fact that extrapyramidal side effects (Marder et al., 2003) and tardive dyskinesia (Miller et al., 2007) have been described even with aripiprazole, albeit at relatively low rates, suggests that partial dopamine agonism therapy is not free of suprathreshold blockade of the dopamine system and compensatory receptor upregulation, at least in subgroups of patients.

In addition, the notion that continued dopamine blockade may be related to worse treatment outcomes through dopamine receptor hypersensitivity is supported by reports suggesting that patients treated with first-generation antipsychotics—particularly haloperidol—are more prone to relapse than patients treated with second-generation antipsychotics that block dopamine less completely (Leucht et al., 2003). While this finding may have been confounded by relatively high doses of haloperidol, similar results have been reported in first-episode patients treated with a modal dose of 3 mg of haloperidol or risperidone (Schooler et al., 2005). The fact that no acute treatment differences were found between the two treatment groups raises the question as to whether or not the detrimental effects of continued “over” blockade of dopamine receptors emerge only after some period of time of continued antipsychotic treatment.

The idea of a “hypersensitivity” or “tardive” psychosis is not new (Chouinard and Jones, 1980). However, the data that are being brought together by Remington and Kapur (Remington and Kapur, 2010) provide a comprehensive theoretical framework, and the authors call for extended dosing as a result of these findings, challenging current thinking and practice. Instead of the usual debate about the amount of antipsychotic given in a day and about the number of doses per day, the authors add a third dimension: the delay between the individual doses extending beyond 24 hours, without intending to stop the drug. Thus, the question is not only how much and how often is needed, but also how often is too much? Obviously, the reverse question will need to be assessed very carefully, too, and that is: how extended is too long? This question could possibly be answered by evaluating the time that it takes for dopamine receptors to recover functionally after different periods of initial blockade. Moreover, should extended dosing be pursued from the beginning of antipsychotic treatment? Or is it better to begin extended dosing only after an initial period of continuous treatment to assure that adequate antipsychotic levels have been achieved in the central nervous system and that sufficient downstream effects and gene expression have taken place? Furthermore, in addition to alternate-day dosing (Remington et al.), different extended dosing options will need to be evaluated. For example, the antipsychotic could be given for three to four days and then stopped for one to three days. In this context, it remains to be clarified what the minimum blood or central nervous system level of a medication is at which the receptors alter or retain their physiological state. This relates also to the question whether there needs to be a gap with zero medication delivery or whether dose levels could alternate between “therapeutic” and very low doses/levels.

Kapur and Remington acknowledge that “one size” will likely not “fit all.” This fits with the call for increasingly individualized treatment that will ultimately have to be based on clinical and, especially, biological markers and predictors. Therefore, it will need to be determined to what degree the duration of continued antipsychotic dosing and the duration of the extended period without antipsychotic dosing is necessary to allow for a functional recovery from the prior dopamine blockade, and how they are influenced by different constant and malleable factors. Candidate variables include the pharmacodynamic and the pharmacokinetic properties of each individual antipsychotic, the illness phase (acute, maintenance, first- or multi-episode), level of prior antipsychotic response, and treatment status (naïve, switch, or restart after a washout period). For example, the efficacy of an extended dosing schedule might well be affected by the affinity of the drug to the dopamine receptor and to other receptors that modulate dopamine transmission. The same is likely true for the half-life of the antipsychotic, which determines the speed and timing of when supra- and sub-therapeutic medication concentrations are reached. Moreover, depending on the affinity and half-life of the antipsychotic, would different peak doses (or levels) need to be given during the “on” phase? And how would this relate to the duration of the “off” phases? An obvious question is whether there are genetic and functional differences between subjects that could determine the duration of the extended dosing and could mandate or even prohibit this strategy.

The idea of allowing the brain to reset and (re)gain its original physiologic state in between pharmacologic manipulation has face validity, and the authors bring to bear a thought-provoking body of evidence. However, hypersensitization of dopamine receptors cannot explain why most or all patients ultimately relapse on continued anti-dopaminergic therapy. Nevertheless, the potentially adverse effect of continuous, non-physiologic dopamine blockade might also relate to another, so far unexplained issue, namely, the superior efficacy of clozapine. Could it be possible that clozapine’s unique efficacy is not due to its pharmacodynamic effect on a crucial and hitherto unrecognized brain receptor or second messenger system, but rather due to its in-built, functionally extended dosing, secondary to the relatively low affinity to dopamine receptors (Ross, 2004)? Clozapine’s lack of superiority in the acute and medium-term treatment of first-episode schizophrenia patients (Lieberman et al., 2003; Woerner et al., 2003) is consistent with this idea (supersensitivity might not have fully unfolded yet in first-episode patients). This possibility is further supported by the reduced risk of tardive dyskinesia with clozapine (Woerner et al., 2003), suggesting a decreased chance of hypersensitized dopamine receptors. However, this line of reasoning leaves unexplained why quetiapine, which shares the low dopamine receptor affinity and fast dissociation properties with clozapine (Kane et al., 1993), does not share its superior efficacy in refractory patients (Kapur and Seeman, 2001).

As posed by the authors, their conceptualization has implications for the current treatment of schizophrenia and psychotic disorders. These considerations also have potentially important implications for the treatment of other disorders in which antipsychotics are used, such as bipolar disorder and unipolar depression, as well as for all chronically administered drug classes used in disorders other than schizophrenia. In addition, as also mentioned by the authors, their viewpoint has relevance for rethinking, or at least reassessing, the development of extended release and depot formulations. It is possible that we pay a price for the gain of decreasing relapses through avoidance of extended treatment gaps by increasing the chance for dopamine hypersensitivity breakthrough psychosis. Therefore, the possibility of avoiding the upregulation of dopamine receptors through extended dosing is intriguing. However, at the same time, this paradigm also raises additional challenges regarding already suboptimal levels of medication adherence if the regularity of drug ingestion is not to be maintained. Clearly, this problem could be relatively easily remediated by producing blister packs with placebo pills interspersed in between active pills, in which the blister cells are numbered in the sequence of the prescribed ingestion. However, a related complication arises: how to adjust the medication schedule when a patient misses an active or placebo dose or dose cycle?

The questions raised above indicate that, while the concept of extended dosing is clearly intriguing and thought provoking, it is not yet ready for prime time. Difficulties regarding the duration and determinants of the “on” and the “off” dose cycle will need to be resolved first in controlled studies. Nevertheless, the conduct of such studies is clearly stimulated by the line of research that Remington and Kapur have brought to bear. Until such data become available, it seems to be best to stick to the conservative regimen of daily dosing. It also seems to be prudent, however, to try staying below the clinical extrapyramidal threshold, which is a good clinical indicator for inducing functional and, likely, even structural dopamine hypersensitivity. After all, the hand writing test by Haase (Haase et al., 1974), developed to determine the “neuroleptic threshold,” which can serve as a “poor man’s PET scan” to guide antipsychotic dosing, might come in “handy” again. However, we are not just coming full circle. Remington and Kapur add to the recognition of the importance of an upper threshold idea that should not be surpassed by the notion of a lower neuroleptic threshold that might need to be undercut before dopamine blockade should be reinitiated again.

The effort to optimize atypical antipsychotic treatment continues to stimulate a significant number of hypotheses and studies within the field of antipsychotic therapy. "Second-generation" or atypical antipsychotics have been analyzed in order to extrapolate possible relationships between the therapeutic benefits of atypical antipsychotics and their ability to mitigate schizophrenia symptoms. It was proposed that a correct receptor D2/HT2 ratio might provide an advantage in antipsychotic therapy in terms of efficacy and tolerability (Leysen et al., 1993). Furthermore, Kapur et al reported on the clinical relevance of correct D2 receptor occupancy levels in order to obtain an optimal ratio between positive symptoms control and extrapyramidal side effects incidence (Kapur and Remington, 2001).

Recent attempts to improve antipsychotic therapy focus on the variable of “time” (the dissociation rate from the receptor, occupancy level overtime, drug half-life, etc.). In line with this research, Remington and Kapur propose a stimulating discussion about the possibility of improving the efficacy of antipsychotic drugs acting on the “time between administrations,” while questioning the need for stable antipsychotic plasma levels.

In our opinion, the time between administrations, or in general, the clinical benefits that might arise from the modulation of the pharmacokinetic (PK) parameters of an antipsychotic, cannot be disjointed from the properties of each drug (as normally accepted for drug-dosage determination). Although both typical and atypical antipsychotics might induce adequate control of positive symptoms at comparable D2 receptor occupancy levels, this finding does not necessarily mean that these drugs act through the same mechanism of action or behave similarly when PK parameters are changed. Atypical antipsychotics are characterized by a high affinity for several receptors (5-HT, a, H, M receptor) that should be taken into account in evaluating the ability of these drugs to reduce the complex symptoms of schizophrenia, particularly when different drug formulations or treatment protocols are adopted. Tonic versus phasic dopamine activity could be differently modulated by antipsychotic compounds, as the ratio between D1 and D2 transmission in the cerebral cortex and basal ganglia may be altered.

Kapur and Remington also indicated that atypical antipsychotics are characterized by significantly different dissociation rates (Koff) from D2 receptors, and that these rates were associated with specific advantages/disadvantages in antipsychotic therapy (Kapur and Seeman, 2000; Kapur and Remington, 2001). Considering the relationship between Koff and availability of the drug to the receptor, it can be realistically hypothesized that these drugs could behave differently when fluctuations of drug plasma levels are modified. Also, one ought to consider that antipsychotic drugs are characterized by differing abilities to cross the blood-brain barrier; therefore, the relationship between brain D2 receptor occupancy and drug plasma levels could also be affected when dosing regimens are modified.

Kapur and Remington also posit that the D2 receptor occupancy of some oral antipsychotics falls below the recommended threshold after several hours from drug administration, suggesting that continuous exposure is not always required (Remington and Kapur, 2010). However, the fact that D2 receptor occupancy levels might fall below the therapeutic threshold during the day is often a consequence of the necessity to avoid excessive peaks of drug plasma levels and related side effects. Furthermore, atypical antipsychotics showing a rapid decline of D2 receptor occupancy have been associated with a high rate of relapse occurrence after treatment discontinuation (Seeman and Tallerico, 1999).

Further investigations are needed to establish whether all antipsychotic compounds associated with formulations providing stable D2 receptor occupancy might provide clinical benefits versus antipsychotic treatments characterized by a significant decline of D2 receptor occupancy during the day. It is still unclear as to whether clinical advantages might come from haloperidol decanoate versus oral immediate formulations of the same drug. However, clinical analyses consistently indicated that symptom improvements and reduced side effects can be observed in schizophrenic patients that switched to long-acting injectable risperidone therapy after having been treated with oral risperidone (Schmauss et al., 2007; Yatham et al., 2007). Recently, new formulations of other atypical antipsychotics that provide smooth drug plasma levels (extended-paliperidone, paliperidone palmitate, olanzapine pamoate, extended-release quetiapine) were introduced into clinical practice. It would be interesting to evaluate the clinical advantage provided by these drugs when compared to immediate-release formulations. From this perspective, clinical comparisons are needed to better understand how PK modifications might alter the efficacy/tolerability profile of each drug.

Remington and Kapur suggested that there might be benefits to non-continuous antipsychotic therapy. Particularly, they highlighted the possibility that continuous versus transient antipsychotic exposure may 1) diminish antipsychotic efficacy across time, and 2) increase the risk of tardive dyskinesia. This is an interesting point; however, the evidence available to support these hypotheses is questionable.

The fact that continuous haloperidol treatment, but not repeated alternate-day dosing, resulted in a progressive recovery of spontaneous rodent motor activity clearly indicated that the two administration protocols possess different tolerance levels. However, the observed recovery of spontaneous rat motor activity could be regarded as a reduction of drug-induced motor disturbance or apathy rather than of antipsychotic efficacy. Further, the behavioral effect induced by antipsychotic drugs in conditioned avoidance response tests was maintained in animals receiving transiently high antipsychotic treatment, while it diminished over time during continuous antipsychotic exposure. However, the dosage and frequency of administration ought to be carefully analyzed before attempting an extrapolation of these preclinical data to clinical practice.

In a constructive analysis of rat dosing regimens that could approximate the optimal D2 receptor occupancy achieved with 24-hour dosing of antipsychotics in humans, Kapur and collaborators indicated that very frequent drug administrations (about one dosage every three to four hours) should be administered to laboratory animals in order to mimic human daily antipsychotic therapy (Kapur et al., 2003). Using this administration procedure, we found that stable antipsychotic efficacy was induced over time by continuous paliperidone infusion or long-acting risperidone administration in the animal model of amphetamine-induced hyperlocomotion (Marchese et al., 2009; 2010). Conversely, it was observed that repeated risperidone injections (one dose every four hours) were associated with a rise in motor side effects during the peak of drug plasma levels (and of striatal D2 receptor occupancy) followed by inadequate antipsychotic efficacy when plasma levels (and D2 receptor occupancy) declined (Marchese et al., 2009; 2010).

It is interesting to note that behavioral tolerance in the conditioned avoidance response test was avoided using a once-a-day administration protocol in rats (Samaha et al., 2008). However, according to Kapur (Kapur et al., 2003), this drug treatment should correspond to a once-a-week administration in humans. Even considering the hypothesis that tolerance to antipsychotic efficacy might occur in humans, which frequency of administration should be applied to optimize antipsychotic treatment? Can this be applied to all patients or it should be individualized for each case?

One of the main features of schizophrenia is still the impossibility to predict symptom development and occurrence. When choosing the antipsychotic administration protocol, we can only empirically determine relapse prevention. Albeit, it is possible that clinical benefits might come from intermittent dosing; however, the applicability of this therapeutic strategy to large samples of patients should be demonstrated, particularly taking into account that relapse might cause dosage adjustment, hospitalization, and altered clinical outcome. For instance, a recent study involving first-episode patients indicated that rates of relapse and deterioration were significantly higher in patients receiving an intermittent antipsychotic treatment than in those receiving maintenance treatment (Gaebel et al., 2010).

In their paper, Remington and Kapur proposed an intriguing discussion on how the variable “time between administrations” can be adjusted in order to optimize antipsychotic therapy. In our opinion, however, this variable cannot be considered independently from the mechanism of action in each drug, nor can it be considered independently of the complex features of schizophrenia. Lastly, the transferability of their theoretical hypothesis to clinical practice remains a daunting task.

This manuscript by Remington and Kapur (2010) raises some...
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This manuscript by Remington and Kapur (2010) raises some interesting and unconventional (“any strategy other than continuous antipsychotic exposure…seems tantamount to heresy”) questions about the potential risks and benefits of prescribing intermittent antipsychotic treatment. The potential strategy of intermittent dosing (either scheduled medication holidays or dosing less frequently than daily) is explored as a theoretical option to reduce side effects and/or reduce likelihood of tolerance/lower effectiveness of a dose.

I'd like to pose a few comments about this theoretical dosing option. First, it is important to consider that antipsychotic medications are often prescribed concurrently with other psychotropic medication. The duration of time between dosing should also be considered in terms of potential impact on drug interactions. Yanofski’s (2010) article on the concurrent use of stimulants and antipsychotics in which the “the dopamine dilemma” is articulated raises concerns about the need to further study how dosing/discontinuation of one agent may impact the efficacy and side effects of the other agent that also affects the dopamine system. Secondly, intermittent antipsychotic dosing may affect medication adherence. While the authors acknowledge this possible concern, it is important to underscore that increased complexity of a medication regimen (e.g., intermittent vs. continuous dosing) and the inability to detect gradual decline in functioning during periods of discontinuation may affect adherence. These issues are especially relevant for individuals with residual cognitive impairment and psychotic symptoms. Thirdly, a note of caution to emphasize that intermittent dosing strategies have not been well studied in randomized controlled trials. Cochrane reviews on management of antipsychotic sexual side effects (Berner et al., 2007) and tardive dyskinesia (Soares-Weiser and Rathbone, 2006) report that medication holidays have been used at times clinically, but have not been studied in a randomized trial. The authors of this manuscript make a strong argument for the need to study dosing duration for specific patient populations to optimize the risk-benefit ratio of optimal treatment. These comments do not contradict this recommendation, but rather emphasize the need for rigorous evaluation of the impact of alternative dosing on adherence, drug interactions, and symptom stability.

Intermittent dosing of antipsychotic drugs: pharmacokinetic and relapse time-course considerations
Remington and Kapur propose that less-than-daily antipsychotic drug administration might be helpful for many patients. They state, “Does this mean we need to (or should) administer antipsychotics at least daily? There is a body of evidence challenging this long-established clinical axiom….”

They cite clinical findings from a paper published in 2005 (Remington et al., 2005) as well as one in press, which demonstrate that every-other-day dosing might be suitable for some patients. The authors’ main scientific rationale is that continuous occupancy of D2 receptors might be deleterious.

A pharmacokinetic primerI note that many of the drugs used in the 2005 paper (as well as most clinically approved antipsychotic drugs) have relatively long biological half-lives:

The reader should be aware that five biological half-lives are required to eliminate 97 percent of the parent compound and thereby eliminate essentially all D2 binding. For most antipsychotic drugs, this would require a one- to several-week “drug holiday.”

Comment
It is not surprising that every-other-day dosing of compounds with relatively long biological half-lives might be associated with no worse outcome than daily dosing—particularly when relatively high doses of drugs are administered. Indeed, one can speculate that a better outcome might predominate—particularly if individuals were subjected to high initial doses of medications.

What is not evident, however, is whether less frequent dosing regimens will lead to sufficiently lower D2 occupancy levels to be clinically relevant. This concern is based on relatively trivial pharmacokinetic considerations. In support of this concern, I remind the readers that therapeutic doses of risperidone and olanzapine apparently still occupy >70 percent of striatal D2 receptors as long as 48 hours after the last dose (Tauscher et al., 2002) (i.e., one to two half-lives).

Consider intermittent dosing of antipsychotics, but tread with caution!
Remington and Kapur (Remington and Kapur, 2010) ask a thought-provoking question: do we need to (or should we) administer antipsychotics at least daily? This is a valid question given that daily antipsychotic treatment has become the standard of care by default, but without solid supporting evidence. We agree that intermittent antipsychotic therapy was perhaps prematurely abandoned and see many good reasons to reconsider it.

First, historically the concern about worsening tardive dyskinesia was an important reason for moving away from the intermittent dosing strategy (van Harten et al., 1998). Though it is unclear whether the newer generation of medications is more efficacious over those available in the 1970s (Jones et al., 2006; Lieberman et al., 2005), it is hard to dispute that as a group, the newer agents pose lesser risk for tardive dyskinesia (Jindal et al., 2008; Nasrallah, 2006). If tardive dyskinesia was indeed a factor in intermittent antipsychotic treatment not getting a foothold, it is high time we revisit the issue, especially now that some of the newer agents have lost their cost disadvantage with the lapse in patent protection.

Third, most clinicians know that at least a subgroup of patients wish to stop their medication after stabilization and do so even against medical advice. An intermittent strategy may be more acceptable to such patients, may enhance therapeutic alliance, and may well prove to be better than no treatment.

Though limiting unnecessary treatment exposure and enhancing therapeutic alliance are both laudable goals, endorsing an intermittent approach may reinforce partial treatment adherence for some patients. Moreover, a treatment strategy that deviates from those refined by years of experience should address potential risks. The concern about increased risk of relapse with intermittent approach (vs. continuous treatment) is real. In choosing an intermittent approach, one has to consider multiple factors such as the severity of the previous episodes, prior history of relapses, frequency of therapeutic contact, risk of dangerousness, level of supervision, etc.

These diverse and competing concerns can only be addressed through controlled studies. For example, it will be helpful to know how much treatment is good enough, and how much is better than none.

In establishing the safety of intermittent dosing of antipsychotics, it would be useful to better understand the state markers of acute psychosis, especially the antecedents of relapse. In depression, sleep gets worse before the onset of a new episode (Perlis et al., 1997; Franzen et al., 2010). It would be helpful to have a similar understanding of the psychobiology of relapse in psychosis. Some easy-to-use objective measures would be particularly helpful. In colonic cancer, carcinoembryonic antigen (CEA) is a useful marker for relapse after surgical resection. Such information will make it easier to pick the right time to switch from continuous to intermittent approach and back. Since heterogeneity in disease pathology in schizophrenia and related disorders is a clear barrier to intermittent therapy becoming standard care, greater understanding of the trait-related markers may make it easier to identify a subset of patients who are especially suited for intermittent therapy.

Remington and Kapur’s proposal raises more questions that the field really needs answers for, and soon.

References:

Remington G, Kapur S: Antipsychotic dosing: how much but also how often? Schizophr Bull; 36(5):900-3. Abstract

Directions in Antipsychotic Dosing: Proceed With Caution
Indefinite continuation of antipsychotic medication for schizophrenia is considered standard care, and “compliance” with this recommendation is the focus of a large part of clinical work with this population, and a primary outcome measure in studies evaluating psychosocial interventions. To challenge this, therefore, is indeed as close to heresy as one can get in the pharmacotherapy of schizophrenia. One fundamental question that is often asked of prescribers of antipsychotic medication is whether the prescription is expected to cause any “changes” in the brain. The standard answer is a reassuring “no.” Remington and Kapur remind us that, good intentions aside, antipsychotic medications do indeed induce receptor and downstream changes (Remington and Kapur, 2010), and structural effects of long-term antipsychotic medication have been documented in the literature (Kosten, 1997). The second frequently asked question in clinical practice is regarding tolerance—the question often articulated, inaccurately, as to whether antipsychotics are “addictive.” Here, again, the standard answer is a resounding “no.” The preclinical literature, including classical experiments describing the effect of antipsychotic pre-medication on cocaine self-administration in rodents (Kosten, 1997) have provided a sophisticated elaboration on this answer. Remington and Kapur again remind us that our answer may not be accurate insofar as tolerance is involved. Indeed, prescription surveys have consistently demonstrated an inverted “U”-shaped effect of age on prescribed dose of antipsychotic (Uchida and Mamo, 2009). While such “snapshots” in time are limited by their cross-sectional design, they do suggest that the dose that got an individual well in early adulthood may not be the same dose that keeps him/her well in mid-life—suggesting a progressive change in the course of the illness, and lending support to the preclinical literature on sensitization. Remington and Kapur (Remington and Kapur, 2010) provide some general directions to address the question of intermittent dosing, including reference to recent preliminary studies on the safety of intermittent dosing.

In addition, psychiatry ought to consider social and ethical implications of not only “where” to go, but “how” to get there. For “heresy” to emerge, dogma must of necessity precede it: psychopharmacology must indeed do away with dogma and challenge continuous antipsychotic therapy with some degree of urgency, given the high stakes, as suggested by Remington and Kapur, but it must also do so without destabilizing patients in the process. To do this, we must respect what we already know—including the fact that abrupt discontinuation of antipsychotic medication is associated with a staggering rate of relapse (Gilbert et al., 1995). It is likely that not all patients experience the same degree of sensitization/tolerance to antipsychotic medication, just as it is equally true that not all patients experience tardive dyskinesia from first- and second-generation antipsychotics. Studying the mechanisms for this individual variability should be a priority if we are to advise patients on the best course of continuation treatment. Finally, patients test “intermittent dosing” routinely, likely without informing us for fear of being chastised for their non-compliance with our recommendations. An openness to the possibility of intermittent dosing on our part may go a long way in allowing those patients who indeed do well with such strategies to openly engage in discussion and customize dosing based on individual response.

Acknowledgements
Dr. Mamo is the recipient of an investigator-initiated grant from Pfizer to study the central kinetics of once-daily dosing of ziprasidone.

References:

Remington G, Kapur S. Antipsychotic Dosing: How Much But Also How Often? Schizophren Bull. 2010. Abstract

Thank you very much for the invitation to provide commentary on the article by Professors Gary Remington and Shitij Kapur. The authors rightly point out that there is much discussion in the literature about dosing and receptor occupancy, but less discussion regarding frequency of dosing and the relevance of peripheral and central effects of dosing intervals. The article raises a number of thought-provoking issues and deserves further discussion.

Professor Kapur published a seminal hypothesis in March 2001 suggesting that fast dissociation from the D2 receptor might explain the mechanism of action of atypical antipsychotics. In this paper, Kapur proposed that fast dissociation may make antipsychotics more accommodating of physiologic D2 transmission (Kapur and Seeman, 2001). Based upon this hypothesis, it is reasonable to believe that antipsychotics which spend less time blocking the D2 receptor (due to rapid on-off binding) provide testable advantages over conventional high-potency D2 antagonists. The relationship between D2 receptor affinity (Ki) and its impact on the systematic or cellular processes necessary to interrupt psychosis or to prevent its recurrence is still largely unknown. The assumed benefit of rapid dissociation is that intermittent D2 receptor blockade allows enough physiological dopamine transmission to occur to reduce the incidence of D2 related side effects, while still providing strong antipsychotic efficacy. However, the rapid dissociation mechanism of action provides an overall consistent level of D2 blockade, and is not the same as intermittent dosing regimens or drug holidays.

Influences of psychotropic agents at receptors diverse from D2 may also be responsible for the mechanism of action of atypical antipsychotics. In particular, dissociation from the D2 receptor may be affected by binding at the 5HT2a receptor (Pani et al., 2007). Blockade of serotonin 5HT2a receptors in the four main dopaminergic pathways (mesocortical, mesolimbic, nigrostriatal, and infundibular) has been strongly suggested to increase the release of pre-synaptic dopamine, such that some attributes associated with D2 receptor blockade are tempered.

Pharmacokinetic considerations are also critical. As pointed out in the article, many pharmaceutical companies are currently pursuing extended-release formulations that allow for less peak-to-trough variability and therefore fewer potential adverse events than are associated with peak plasma concentrations. Although extended-release formulations may aid some patients with medication compliance, these extended-release formulations do not provide superior efficacy over oral medications. Efforts published in the current literature that have sought to correlate plasma concentrations with efficacy have not reliably shown a robust correlation for individual patients.

It is important to note that plasma concentrations required for maintenance of efficacy with the depot antipsychotics (in particular, haloperidol, pipotiazine, and zuclopenthixol) generally are 30-50 percent lower than target concentrations achieved with the oral formulations of the same compound (Girard et al., 1984; Nayak et al., 1987; Aaes-Jorgensen, 1989). Therefore, the use of long-acting injectable antipsychotics may provide advantages due to the lower plasma exposure observed over the continuous use of oral medications.

We are aware of seven publications in which discontinuous antipsychotic therapy was compared to continuous therapy. The first two of these publications describe a two-year randomized single-blind comparison of discontinuous oral antipsychotic therapy and continuous antipsychotic therapy. Although preliminary results published in 1987 from this methodology were promising, the final results demonstrated that continuous medication was statistically superior to targeted medication in delaying time to schizophrenia-related relapse and hospitalization (Carpenter et al., 1987; Carpenter et al., 1990).

The third study was conducted in 54 stable schizophrenic patients and compared discontinuous treatment with depot fluphenazine decanoate versus a pre-trial depot neuroleptic (Jolley et al., 1990). Prodromal symptoms were closely monitored in this study, and supplemental oral haloperidol was given as a rescue agent. Patients were followed for two years or until time to first relapse. Although depot treatments were used in this study, a remarkable difference in relapse rates and Kaplan-Meier estimates of time to relapse favored patients who received continuous depot neuroleptic therapy (P = 0.005 and P = 0.023, respectively). The fourth study was a two-year double-blind placebo controlled randomized study comparing discontinuous drug strategy with continuous drug use (Herz et al., 1991). The relapse rates for patients receiving continuous treatment was 16 percent compared with 30 percent in those treated discontinuously. The authors in this study concluded that there was no advantage in using the discontinuous approach.

The fifth and largest study conducted to date to examine this issue was a randomized open-label study comparing continuous treatment with standard antipsychotic therapy (maintenance) with two types of discontinuous treatment (early intervention and crisis intervention). In this study, 364 outpatient schizophrenics were studied over a two-year period. Early intervention strategies consisted of tapering withdrawal of neuroleptics after clinical stabilization and reinitiation at earliest onset of prodromal symptoms. Patients allocated to the crisis intervention group also underwent a tapering withdrawal of antipsychotics, but were restarted on their medication only at the time of a full relapse. Although relapse rates were significantly lower in patients in the early intervention group (49 percent) as compared to the crisis intervention group (63 percent), those patients allocated to continuous treatment had even lower relapse rates (23 percent). Dropout rates and re-hospitalization rates also favored continuous treatment (Pietzcker et al., 1993).

The sixth study was recently published online ahead of print and involved a randomized double-blind study of discontinuous drug treatment with prodromal-based early intervention compared with continuous maintenance treatment on oral antipsychotics (Gaebel et al., 2010). This study was unique in that only patients with a first episode of schizophrenia were included. The primary endpoint was relapse rates between treatment groups. The relapse and deterioration rates were significantly higher in the discontinuous treatment group as compared to the continuous treatment group (P = 0.04 and P <0.001, respectively). Kaplan-Meier estimates of time to relapse also significantly favored continuous treatment over discontinuous (P < 0.001).

Since the original article by Remington and Kapur was published in Schizophrenia Bulletin, results from a double-blind placebo-controlled study by the same authors have been published online (Remington et al., 2010). In this six-month study, a relatively small number of patients (n = 35) were randomized to receive either blinded daily medication of their current treatment as usual (TAU), or were switched to every second day dosing (extended). The primary hypothesis was that there would be no significant difference between the two groups over the course of the trial as measured by the BPRS total score. The primary efficacy parameter was analyzed via ANOVA and used polynomial contrasts to evaluate interactions over time. This analysis seemed to include only completers. A mixed model for repeated measures analysis or even LOCF imputation would have been preferred methodologies. The authors found no significant interactions between linear trend of time and treatment group. The authors acknowledge the small sample size of this study and point out that a power calculation (using 80 percent power at the one-sided 5 percent level) required approximately 40 subjects per treatment group. Despite the fact that the study may have been underpowered, the authors suggest that the “…consistently large P values offer…indirect evidence that lack of statistical power may not be a plausible explanation” for failing to detect differences between the groups. The risk for type II error (failing to reject the null hypothesis when the alternative is true) should always be considered when the null hypothesis is not rejected. Even in a well-powered study, failure to reject the null hypothesis of no treatment difference cannot, in itself, lead to a conclusion of equality between the treatments. For that, a well-designed equivalence or non-inferiority study would be more appropriate. Despite the lack of a significant trend for time for the primary outcome, two findings from this study deserve closer examination. A difference of approximately one point on the BPRS total score in favor of patients in the TAU group is evident at the six-month endpoint, and a numerically greater number of subjects in the extended dosing group relapsed (24 percent [4/17]) as compared to those receiving TAU (17 percent [3/18]). Provided that such a study was designed to detect such a difference, a larger sample would likely have been able to distinguish the true difference between the groups pertaining to this critical outcome.

The evidence cited above tends to support that there appears to be an advantage for the use of continuous medication over discontinuous treatment. This is not to say that there may not be, as the authors point out, individuals who respond to lower doses of medication, others who may be able to stop medication and remain stable for some period of time, and certain patients who may be able to be treated on a targeted basis. However, clinical wisdom would underline that for most patients with schizophrenia, these options are neither practical nor are they recommended. In general, adherence with oral antipsychotics is poor. It has been estimated that up to 40 percent of patients with schizophrenia are poorly adherent with their antipsychotic regimen (Valenstein et al., 2006). This partial or non-adherence leads to lack of pharmacologic target engagement and a predictable host of foreseeable deleterious outcomes and suffering for the patient, including relapse of psychotic symptoms, hospitalization, progressive structural changes in the brain with each subsequent psychotic event, the potential for suicide or violence, and disruption in the lives of patients, families, and their caregivers.

Two other points are worth noting: The first is that short gaps in medication adherence are associated with deleterious clinical outcomes. Compliance to refills of antipsychotics was examined in a retrospective fashion using a cohort of Medicaid patients with schizophrenia (Weiden et al., 2004). As expected, the odds of hospitalization were greatest in patients with a gap in medication of more than 30 days, but interestingly, gaps of one to 10 days were also associated with statistically higher odds of being hospitalized. The second point is that evidence from a retrospective analysis of hospital discharge and drug-dispensation data found that interruption in antipsychotic medication use led to a significantly greater rate of suicide attempts (fourfold) in schizophrenic patients with a drug holiday as compared to patients without drug holidays (Herings and Erkens, 2003).

Early diagnosis, treatment, and reducing the risk of relapse should be the ultimate goal in all patients with schizophrenia. Schizophrenic relapse is a complex clinical phenomenon with multi-factorial causes. We agree with the authors that there is no one-size-fits-all treatment plan. Antipsychotic treatment in our view should be the cornerstone of a treatment plan that addresses psychiatric, medical, psychosocial, substance abuse, and functioning issues.

Relapse is best predicted by medication non-adherence, prior history of relapse, early-onset disease, and poor functioning (Ascher-Svanum et al., 2010). While there may be some patients who do not immediately relapse upon discontinuation of antipsychotic therapy, the vast majority will eventually suffer a recurrence. Several studies have demonstrated that antipsychotic withdrawal followed by rescue antipsychotic therapy at the onset of prodromal symptoms is inadequate to prevent relapse. Without a biomarker to measure disease progression or signs of worsening of disease before onset of prodromal symptoms, we find it difficult to recommend discontinuous antipsychotic therapy. We therefore believe that an adequately designed and powered study to answer this important research question is warranted with appropriate attention to further understanding any subpopulations that would respond to targeted therapy. Although the results from Remington and Kapur’s recent double-blind study show some interesting trends, the small sample size makes the study findings exploratory in nature and deserve to be studied further. We welcome further discussion on this important topic.

Remington and Kapur have raised some important questions that both highlight the limitations of our current knowledge and assumptions and suggest important avenues for further research.

The degree and consistency of D2 occupancy that is required for antipsychotic effect is a critical question influencing routine clinical practice, benefit-risk judgments, and clinical drug development. Remington and Kapur have played an important role in drawing attention these issues.

The brief review of the data on intermittent treatment in relation to both efficacy and adverse effects is informative. As the authors imply, it is critical to identify the type of intermittency to which we are referring. Drug “interruptions/holidays” lasting weeks or months can produce very different effects than the “transient” exposure to which the authors are referring. Where to draw the line becomes an important empirical question. The new clinical evidence that is emerging (largely with the leadership of the authors) is encouraging, and hopefully larger-scale, more definitive research will follow.

It is also important to emphasize the different spectrum of patients whom we treat and the different phases of illness that must be addressed in optimizing dosing in all dimensions. We certainly know that some patients experience robust response to antipsychotic agents, while others derive little benefit. A larger middle group derives important, clinically significant, but not optimum benefit. Addressing issues of dosing must perhaps target each group separately (or at least be capable of carrying out the necessary subgroup analyses). Recent pharmacogenetic (Lencz et al., 2006) work highlights other factors that can influence medication responsiveness, and perhaps examining optimum dosing strategies in those with and without relevant polymorphism would be informative. In addition, Dr. Kapur’s and our work (Correll et al., 2003; Kinon et al., 2008; Kinon et al., 2010) on the early response/non-response paradigm might be helpful in identifying meaningful subgroups for focused attention.

Biomarkers that would help us identify those patients at risk for relapse over the short term after antipsychotic withdrawal is still an unmet need that remains relevant within the context of optimizing dose for maintenance treatment. The reason why some patients “break through” even guaranteed medication (in the form of long-acting injectable formulations) with seemingly adequate D2 receptor occupancy has been a puzzle. However, the notion of antipsychotic tolerance or “supersensitivity psychosis” remains insufficiently examined with appropriate methodology despite its obvious critical implications. Any explanation would also have to account for the apparent fact that the majority of patients don’t break though antipsychotic treatment. Given the general findings (though inconsistent) that relapse rates are lower on long-acting injectable medications than oral medications, it is therefore possible that assured adherence is only one possible explanation, and that the naturally occurring, somewhat diminishing receptor blockade over the injection interval also plays a role.

The relationship between dosing strategies and the incidence/severity of adverse effects is another fertile ground for investigation. We have some data regarding dose response relationships with adverse effects in such domains as tardive dyskinesia (Kane and Smith, 1982) and weight gain (Kane et al., 2010). However, the role of frequency of administration and resulting duration of various relevant receptor effects is worthy of further study.

In summary, we are indebted to Remington and Kapur for their insights and heuristic comments, and hope that the field can begin to help them to further address some of these important questions.

“No thing is without poison. The dosage makes it either a...
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“No thing is without poison. The dosage makes it either a poison or a remedy.”—Paracelsus

Despite the proven efficacy of antipsychotic drugs, their mechanism of action and optimal dosing are not fully determined. Beyond their antagonism of dopamine (DA) at the dopamine 2 receptor (D-2) at some requisite threshold dose, we do not know definitively how they work and at what schedule to optimally administer them (Miyamoto et al., 2005). The paper by Remington and Kapur provides an intriguing formulation of several lines of investigation of the pharmacodynamic actions of APDs and proposes a novel dosing schedule for their administration. The gist of their argument is that continuous APD administration at doses that occupy >60 percent of striatal D-2 receptors is unnecessary and excessive, potentially causing undesirable side effects and tolerance to the drug’s pharmacologic effects. They propose that, rather than continuously blocking D-2 receptors and inhibiting their stimulation by endogenous DA, treatment can be administered to only intermittently occupy and interrupt the putative overactivity in striatal DA neurotransmission. The clinical application of this hypothesis calls for extended dose intervals rather than daily or multiple times daily.

In formulating their thesis, they invoke principles of plasticity, sensitization, and tolerance. Although their argument is intriguing, it has several inconsistencies with prior research and clinical experience as well as practical challenges to its implementation. It should be noted that despite the excessive dosing practices that were previously (and possibly are currently) used, there has not been any convincing demonstration of tolerance developing to the antipsychotic effects of APDs or the behavioral equivalent of tardive dyskinesia (called supersensitivity psychosis) (Kirkpatrick et al., 1992). In addition, it has been observed that patients who miss doses or discontinue clozapine (a drug that has very low D-2 affinity and a short half-life of four to 12 hours, in effect simulating an extended dosing schedule and intermittent administration) are prone to fulminant relapses, suggesting that continuous treatment and sustained occupancy may be necessary (Stanilla et al., 1997; Verghese et al., 1996). Finally, numerous prior attempts to develop intermittent treatment strategies proved unsuccessful due to higher rates of symptom exacerbation than in continuously treated patients (Carpenter, 1996; Schooler et al., 1997).

Nevertheless, Remington and Kapur’s observations and concerns with respect to excessive dosing are cogent. It is sobering indeed to consider the dosing strategies employed by our field historically, and particularly with the older, so-called first-generation APDs (Mason and Granacher, 1976; Quitkin et al., 1975). Thus, the authors' cautionary view and careful analysis of the pharmacodynamic basis of therapeutic effects is welcome. At the same time, the ideas that they propose are not entirely new. Prior investigators have suggested that “tickling” neuroreceptors intermittently was all that was necessary and preferable to a more “heavy-handed” approach (Antelman et al., 1986; Antelman et al., 1997). However, the practical applications of these hypotheses were never proven and were fraught with risk. Similarly, the proposal of Remington and Kapur, intriguing as it may be, entails considerable challenges to prove and potential risk to implement. But that is not to say that it is not worth trying.

We would first like to thank those who took the time to respond to our article. We appreciate the many thoughtful points made and shall respond broadly to the themes that seemed to emerge.

Potential—but safety first
It is reassuring that clinically related concerns were repeatedly raised, ranging from the heterogeneous nature of schizophrenia and lack of markers for subtyping response/outcome to the very preliminary nature of our hypotheses, limited clinical data, and practical concerns (e.g., problems that arise with not taking medications daily). These points are all valid, but it remains that we have at least preliminary data indicating there may be a subgroup that will do at least as well, and possibly better, with alternative strategies to daily dosing. This cannot be ignored, especially in the face of current interest in individualized medicine.

We do echo the concerns of others around the need for further carefully controlled studies and agree that, beyond replication, there are numerous nuances that warrant consideration. What constitutes a “safe” interval between dosing (it, too, is unlikely to be “one size fits all”)? As noted in one comment, our understanding of drug half-life would suggest that medication gaps can be even longer, at least in some compounds, and we would not disagree; for obvious reasons, we chose a conservative approach in initiating this work. Is dose reduction during the gap safer than dose discontinuation? Do the clinical benefits clearly outweigh risks, especially in the absence of available markers that might identify potential candidates? As several commented, it is heuristically appealing to tie this line of work, in conjunction with concepts such as tolerance, to changes at the level of the CNS which may be used in parallel as yardsticks to guide our research.

D2 isn’t everything—but it’s the best we’ve got
We acknowledge this work has been driven by an approach largely fueled by the dopamine D2 story, but stand by the value of these data in setting the stage for questions related to dosing intervals and tolerance. However, this should not be misinterpreted as suggesting that we dismiss the role of other receptors or systems in an illness as complex as schizophrenia, or their potential value in its pharmacotherapy.

Extended is not intermittent or targeted
We reiterate that our notion of extended antipsychotic dosing is unrelated to “intermittent” or “targeted” therapy. It is regular treatment—much like daily dosing or a depot—it is just that the interval is different. In line with this, we see less value in the search for clinical markers that might portend clinical deterioration, an identified goal with intermittent therapy. The greater value will come from biologic markers allowing us to individualize antipsychotic treatment on a variety of dimensions (e.g., choice, dose, dosing interval, duration, etc.).

Extended dosing and tolerance—a tale of two stories
Finally, we have packaged extended dosing and tolerance within the same argument—they make a nice theoretical fit. At the same time, it is simply too early to make them the same story (although it’s safe to say they should keep a close eye on each other).

Remington and Kapur have challenged the existing dogma of...
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Remington and Kapur have challenged the existing dogma of the need for continuous daily dosing of antipsychotic medication and present several compelling arguments in favor of an extended dosing strategy. Our experience at the UCLA Aftercare Research Program has been that, even in our very carefully controlled research setting, two-thirds of recent-onset schizophrenia patients will experience some level of non-adherence over an 18-month period (Subotnik et al., 2011). In many cases, the non-adherence was partial and/or brief. One might say that we should “listen” to this finding because it tells us that most patients might not want to take antipsychotic medication, or at least not at the dosage usually prescribed. However, it also suggests that adherence with an extended dosing regimen would also confront similar problems with many schizophrenia outpatients. As Remington and Kapur note, adherence with a more complex schedule of every-other-day dosing might be even more challenging than daily dosing. Something that was quite striking in our data was that even brief periods of partial non-adherence led to greater risk of relapse than is commonly assumed. It is possible that the current clinical practice of prescribing the lowest amount of psychiatric medication to control symptoms while keeping side effects at a minimum might be contributing to a situation in which there is very little allowance for even partial non-adherence. If this is the case, then it is likely that an extended dosing strategy might put patients even further “on the edge” and even more vulnerable to exacerbation or relapse following periods of either brief or partial non-adherence.

An extended dosing strategy might be applicable to selected highly adherent outpatients, like those chosen for the study by Remington et al. (2010). However, to succeed, one would need to be able to identify accurately which patients are likely to continue to be fully adherent to their antipsychotic medication as prescribed. This task is not as easy as it might seem. Schizophrenia patients often lack insight into the continued need for antipsychotic medication and either covertly or overtly stop taking some or all of their medication. Therefore, poor awareness of having a mental disorder that requires antipsychotic medication seems like a likely candidate for prediction, and our preliminary data suggest that there might be some traction there. Other candidate variables for prediction of non-adherence include substance use, male gender, younger age, non-white race, history of more frequent hospitalizations, more severe baseline hostility, agitation and psychosis, greater cognitive impairment, poor medication efficacy, medication side effects, lack of family support, and negative attitudes towards antipsychotic medication (Leucht et al., 2006; Valenstein et al., 2006; Weiden, 2007; Yamada et al., 2006). We don’t currently know how accurately some combination of variables could identify consistently adherent outpatients who might be candidates for an extended dosing strategy.

Our preliminary data show that adherence to long-acting injectable risperidone is excellent (Subotnik et al., 2009), and therefore that the long-acting injectable mode of administration is able to override most or all factors that typically contribute to non-adherence with oral antipsychotic medication. Further, long-acting injectable risperidone is showing superior relapse prevention compared to oral administration of the same medication. Thus, it seems like a head-to-head comparison of the extended dosing strategy and a long-acting injectable antipsychotic medication is in order to see which strategy is more advantageous with regard to exacerbation/relapse risk, side effects, and cognitive functioning.